Substituted benzoic acids, their salts and esters



Patented Feb. 16, 1 954 SUBSTITUTED BENZOIC ACIDS, THEIR SALTS" AND ESTERS Quentin E. Thompson, St. Louis,vMo.,

Monsanto Chemical Company, St.

assignor to Louis, Mo.,

a corporation of Delaware No' Drawing. Application December 7, 1951, Serial No. 260,569

9 Claims.

This invention, relates to (alkyl-l-piperidylsulfonyD-benzoic acids, preferably wherein the alkyl group contains from 1 to carbon atoms, their salts. and esters, and to a method for their preparation. The (alkyl 1-piperidylsulfonyl).- benzoic acids may be represented by the following formula wherein R represents an alkyl radical, preferably containing from 1 to 5 carbon atoms. The letter 5 in the formula above indicates asaturated ring structure.

The (2 alkyl 1 piperidylsulfonyl)benzoicv acids and the (3-alkyl-l-piperidylsulfonyl)benzoic acids, their salts and esters, as described above, contain an asymmetric carbon atom. As a result thereof, these compounds exist in two optically active forms, namely, the deXtro-rotary (d) and levo-rotary (Z). All suchv forms and mixtures of these isomers, as well as the 1- alkyl 1 piperidylsulfonyl)benzoic acids, their salts and esters, which do not contain an asymmetric carbon atom, are contemplated as coming within the scope of this invention. All of the novel compounds of this invention can be used as intermediates for the preparation of various types of organic compounds. The optically active compounds just referred to may be used as.

resolving agents or as intermediates for the preparation of other optically active organic compounds. For example, they are useful in the preparation of such resolving agents as the optically active (alkyl-l-piperidylsulfonyl) benzoyl halides, the preparation of which being described in my co-pending application Serial No. 260,568, filed December 7, 1951.

The expression salts of (alkyl-l-piperidylsulfonyDbenzoic acids is meant to include the alkali metal and alkaline earth metal salts such as sodium, potassium, lithium, ammonium, magnesium, calcium, the salts of other metals such as copper and iron, and the substituted organic ammonium salts such as the salts of methylamine, trimethylamine, triethylamine, diethylamine, monoethanolamine, triethanolamine, isopropanolamine, pyridine, a-phenylethylamine, morpholine, ephedrine, guanidine, the quaternary ammonium salts such as the tetramethyl ammonium salt, and the like.

The expression esters of (alkyl-l-pip'eridylsulfonyDbenzoic acids" is meant to include any ester of (alkyl-l-piperidylsulfonyl)benzoic acid with any monohydric orpolyhydric'al'cohol which may be either saturated or unsaturated. Typical of such alcohols are primary alkyl alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, amyl alcohol, hexyl alcohol, hept'yl' alcohol, octyl alcohol, nonyl alcohol, decyl alcohol, undecyl alcohol, dodecyl alcohol, tetradecyl alcohol, cetyl alcohol, and octadecyl alcohol; secondary alkyl alcohols such as isopropyl alcohol, secondary butyl alcohol, secondary amyl alcohol, secondary hexyl alcohol, secondary" octyl alcohol and secondary nonyl alcohol: tertiary alkyl alcohols such as-tertiary butyl alco-- hol, tertiary amyl alcohol, tertiary butyl carbinol and tertiary amyl carbinol; the ether alcohols such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and ethylene glycol mono-Z-ethylhexyl ether; aromatic alcohols such as benzyl alcohol and methylphenylcarbinol; alicyclic alcohols such as cyclohexanol, cyclobutyl carbinol and cyclopentanol'; heterocyclic alcohols such as furfuryl and tetrahydrofurfuryl alcohols; unsaturated aliphatic alcohols such as allyl alcohol, methallyl alcohol, crotyl alcohol and propargyl alcohol; substituted alcohols such asethylene chlorohydrin, cyanoh-yd'rin and 2-bromoethano'l; polyhydric alcohols. such as. ethyleneglycol, diethyleneglycol, glycerol, erythritol, pentaerythritol, and the like.

The novel esters of this invention may be prepared by esterifying (alkyl-l-piperidylsulfonyl)- benzoic acid with an alcohol. Inthe case ofv the methyl ester, a particularly convenient method. of preparation comprises reacting an (alkyl-1- piperidylsulfonyl) benzoic acid and diazomethane. The novel salts of this invention may be prepared by neutralizing an (alkyl-l-piperidylsulfonyl benzoic acid with an alkaline derivative of a salt-forming group. The (alkyl-l-piperidylsulfonyDbenzoic acids of this invention may be prepared by reacting a l-(cyanophenylsulfonyl) alkylpiperidine having'the formula @iQa wherein R represents an alkyl radical, preferably containing from 1 to 5 carbon atoms, and an alkaline derivative of a salt-forming group, thereby forming a salt of an (alkyl-l-piperidylsulfonyDbenzoic acid which may be converted into the free acid by neutralization with a mineral acid. Instead of neutralizing the salt of the 3 (alkyl-l-piperidylsulfonyl)benzoic acid with a mineral acid and recovering the free acid, the salt of the (alkyl-l-piperidylsulfonyl)benzoic acid may be recovered directly.

The following examples are illustrative of the novel compounds of this invention and their method of preparation:

EXAMPLE I S Calculated for C13H17NO4S 11.32 Found 11.28

EXAMPLE II The procedure set forth in Example I is repeated utilizing the following ingredients:

32 g. of d-l-(p-cyanophenylsulfonyl)-2-methylpiperidine 400 ml. of 10% solution of sodium hydroxide The reaction mixture thus obtained is poured into a mixture of cracked ice and hydrochloric acid, precipitating approximately 34 g. of 01- (2-methyl-l-piperidylsulfonyl) benzoic acid which is recovered by filtration and dried. This acid has the following properties:

Melting point, 19l192 C. Optical rotation [c] =+36.96 (:2, chloroform) EXAMPLE III The procedure set forth in Example I is repeated utilizing the following ingredients:

32 g. of l-l-(p-cyanophenylsulfonyl)-2-methylpiperidine 400 m1. of solution of potassium hydroxide The reaction mixture thus obtained is poured into a mixture of cracked ice and hydrochloric acid, precipitating Z-p-(2-methyl-l-piperidylsulfonyl) benzoic acid which is recovered therefrom by filtration, and recrystallized from chloroform. This acid has the following properties:

Melting point, l91-192 C. Optical rotation [a] =-36.9 (c=2, chloroform) EXAMPLE IV The procedure set forth in Example I is repeated utilizing the following ingredients:

29.2 g. of d-l-(p-cyanophenylsulfonyl)-2-propylpiperidine 350 m1. of 15% The reaction mixture thus obtained is poured into a mixture of cracked ice and hydrochloric solution of sodium carbonate acid, precipitating cZ-p-(2-propyl-l-piperidylsulfonyDbenzoic acid which is recovered therefrom andpri r r EXAMPLE V The procedure set forth in Example I is repeated utilizing the following ingredients:

32.1 g. of d-l-(m-cyanophenylsulfonyl) -2-pentylpiperidine 400 ml. of 15% solution of potassium carbonate The reaction mixture thus obtained is poured into a mixture of cracked ice and hydrochloric acid, precipitating d-m-(2-pentyl-l-piperidylsulfonyl)benzoic acid which is recovered therefrom by filtration and dried.

EXAMPLE VI The procedure set forth in Example I is repeated utilizing the following ingredients:

26.4 g. of 2-1-(p-cyanophenylsulfonyl)-3-methylpiperidine 350 ml. of 10% solution of sodium hydroxide The reaction mixture thus obtained is poured into a mixture of cracked ice and hydrochloric acid, precipitating Z-p-(3-methyl-lpiperidylsulfonyDbenzoic acid which is recovered therefrom by filtration and dried.

EXAMPLE VII The procedure set forth in Example I is repeated utilizing the following ingredients:

26.4 g. of 1-(o-cyanophenylsulfonyl)-4-methylpiperidine 350 m1. of 10% solution of sodium hydroxide The reaction mixture thus obtained is poured into a mixture of cracked ice and hydrochloric acid, precipitating o-( i-methyl-l-piperidylsulfonyDbenzoic acid which is recovered therefrom by filtration and dried.

EXAMPLE VIII A mixture of 26.4 g. of dZ-l-(p-cyanophenylsulfonyl)-2-methylpiperidine and 350 ml. of a 10% sodium hydroxide solution is refluxed for approximately 2 /2 hours. On cooling the reaction mixture, the sodium salt of dZ-p-(2-methyll-piperidylsulfonyl)benzoic acid is precipitated which is recovered therefrom by filtration and dried.

EXAMPLE IX An excellent yield of ammonium d-p-(2- methyl-l-piperidylsulfonyl)benzoate is obtained by neutralizing 28.3 g. of Z-p-(Z-methyl-l-piperidylsulfonybbenzoic acid with 25.0 ml. of a 4 molar ammonium hydroxide solution and removing the water by distillation under reduced pressure.

EXAMPLE X An excellent yield of calcium d-p-(3-ethyl-1- piperidylsulfonyl)benzoate is obtained by neutralizing 28.3 g. of d-p-(3-ethyl-1-piperidylsulfonyl benzoic acid with 2.8 g. of calcium oxide in x ml. of anhydrous methanol and removing the excess methanol by distillation under reduced pressure.

EXAMPLE x1 An excellent yield of the pyridine salt of o-(4- propyl-l-piperidylsulfonyl)benzoic acid is obtained by dissolving 31 g. of o-( i-propyl-l-piperidylsulfonyDbenzoic acid in ml. of dry pyridine and allowing the solution to cool. In

the pyridine salt crystalwashed the absence of moisture, lizes out and is removed by filtration,

with anhydrous etherand' dried.

' EXAMPLE XII Methyl d p (Z-methyl-l-piperidylsulfonyl) benzoate is obtained by slowly adding, in increments, a solution comprising 80 ml. of ether and 5 g. of diazomethane to 28.3 g. of d-p-(Z-methyll-piperidylsulfonyl)benzoic acid suspended in about 250 ml. of ether. Immediate reaction occurs and the slow addition of the diazomethane solution is continued until the yellow color of diazomethane persists, thereby indicating that all of the acid has been consumed. A large proportion of the excess ether is then distilled from the reaction mixture and a small amount of petroleum ether added, precipitating the desired methyl ester. The methyl ester is recovered by filtration and recrystallized from petroleum ether. Methyl d p (Z-methyl-l-piperidylsulfonyDbenzoate has the following properties:

Melting point, 102103 C. Optical rotation [a] =+34.3

form) (0:2, chloro- EXAlVIPLE XIII.

Isopropyl Z p-(z-inethyl-l-piperidylsulfonyl) benzoate is obtained by reacting 28.3 g. of Z-p-(2- methyl-1-piperidylsulfonyl)benzoic acid and 150 g. of isopropyl alcohol, and removing the water of esterification and the excess isopropyl alcohol by azeotropic distillation.

EXAMPLE XIV In accordance with the procedure described in Example XIII, an excellent yield of ethylene glycol bis [d-m(3-pentyl-1-piperidylsulfonyl)- benzoate] is obtained utilizing the following ingredients:

10 g. of d-m-(3-penty1-l-piperidylsulfonyl) benzoic acid g. of ethylene glycol While the preceding examples have illustrated specific embodiments of this invention, it will be obvious to those skilled in the art that the reactants and reaction conditions specified in these examples are subject to substantial variation within departing from the scope of this invention. For example, the reaction of the 1- (cyanophenylsulfonyl) -alkylpiperidine and the alkaline derivative of a salt-forming group may be carried out in a wide variety of inert reaction mediums. Water, alkyl alcohols, ethylene glycol, etc., are illustrations of inert reaction mediums which may be used.

The reaction of the l-(cyanophenylsulfonyD- alkylpiperidine and the alkaline derivative of a salt-forming group may be carried out over a substantial temperature range, such as at a temperature in the range of from about 60 C. to about 150 C. Preferably, the reaction is carried out by boiling the reaction mixture under reflux conditions. In this reaction the quantities of the reactants utilized is also subject to substantial variation. While equivalent proportions of reactants may be utilized if desired, it is found particularly desirable to use an excess of the alkaline derivative of a salt-forming group. From about 2 to about 10 equivalent proportions of the alkaline derivative of a salt-forming group for each equivalent proportion of the 1-(cyanophenylsulfonyl) -alkylpiperidine is particularly advantagcous.

While any alkaline derivative of a salt-forming group can be utilized in this reaction, the carbonates and hydroxides of the desired salt-forming groups are particularly applicable.

The neutralization of the (alkyl-l-piperidylsulfonyl)-benzoic acid with an alkaline deriva tive of a salt-forming group to form the novel salts of this invention or the esterification of the (alkyl-l-piperidylsulfonyl)benzoic acid with an alcohol to form the novel esters. of this invention may be carried out in accordance with any of the standard neutralization or esterification techniques well known to those skilled in the art.

The 1- (cyanophenylsulfonyl) -alkylpiperidines: utilized in. preparing the novel compounds of this invention. are described and claimed in my copencling application Serial No. 256.137. filed November 13, 1951.

What is claimed is:

1. As new compositions of matter, compounds of the group; consisting of optically active: (alkyl- 1-piperidylsulfonyl)--benzoic acids, their metal; salts, their ammonium and their substituted ammonium salts, said acids having the formula wherein R is a lower alkyl radical and whereinthe alkyl-l-piperidylsulfonyl radical is selected from the group consisting of 2-alkyl-1-piperidylsulfonyl and 3-alkyl-l-piperidylsulfonyl radicals.

2. As new compositions of matter optically active (2-alkyl-l-piperidylsulfonyl)-benzoic acids having the formula where R is an alkyl radical containing from 1 to 5 carbon atoms.

3. As new compositions of matter optically active (3-alkyl-l-piperidylsulfonyl)benzoic acids having the formula @ggt where R is an alkyl radical containing from 1 to 5 carbon atoms.

4. As a new chemical compound, optically active p-(Z-methyl 1 piperidylsulfonyl)benzoic acid.

5. As a new chemical compound, optically active sodium p-(2-methyl 1 piperidylsulfonyl) benzoate.

6. In a process for the preparation of the compounds of claim 1 the step comprising reacting an optically active 1 (cyanophenylsulfonyl) alkylpiperidine having the formula wherein R is a lower alkyl radical and wherein the alkyl-l-piperidylsulfonyl radical is selected from the group consisting of 2-alkyl-1-piperidylsulfonyl and 3-alkyl-1-piperidylsulfony1 radicals, with a, basic compound selected from the group consisting of salt forming metallo, ammonium and substituted ammonium hydroxides and carbonates.

7 7. In a process for the preparation of the compounds of claim 2 the steps comprising reacting an optically active l-(cyanophenylsulfonyl)-2-alkylpiperidine having the formula where R is an alkyl radical containing from 1 to 5 carbon atoms, with a hydroxide of an alkali metal to form the alkali metal salt of the (3 alkyl-l-piperidylsulfonyl) -benzoic acid and neutralizing the salt so formed with a mineral acid.

9. In a process for the preparation of optically active p- (Z-methyl-l-piperidylsulfonyl) -b enzoic acid, the steps comprising reacting optically active 1(p-cyanophenylsulfonyD- -methylpiperidine with a hydroxide of an alkali metal to form the alkali metal salt of p-(2-methyl-1-piperidylsulfonyD-benzoic acid, and neutralizing the salt so obtained with a mineral acid.

QUENTIN E. THOMPSON.

References Cited in the file of this patent UNITED STATES PATENTS Abstracted Chem. Fieser and Fieser Abst, vol. 41, pp. 727-731. Organic Chemistry (1944) 

1. AS NEW COMPOSITIONS OF MATTER, COMPOUNDS OF THE GROUP CONSISTING OF OPTICALLY ACTIVE (ALKYL1-PIPERIDYLSULFONYL)-BENZOIC ACIDS, THEIR METAL SALTS, THEIR AMMONIUM AND THEIR SUBSTITUTED AMMONIUM SALTS, SAID ACIDS HAVING THE FORMULA 